Myasthenia-like paraneoplastic syndrome with multiple cranial nerve tumor infiltration: A case report and literature review

Rationale: Approximately 0.001% of patients with cancer have paraneoplastic nerve system syndrome, which can affect the central nervous system, neuromuscular junction, or peripheral nervous system. Although myasthenia gravis (MG) may exist as a thymic paraneoplastic syndrome (PNPS), its association with primary lung cancer remains unknown. Patient concerns: A 55-year-old female presented with slurred speech, weakness in chewing, sporadic difficulty in swallowing, and weakness in both lower limbs for half a year. Diagnoses: Based on cerebrospinal fluid and electromyography findings, we present the case of a female patient diagnosed with overlapping multicranial nerve tumor infiltration and MG-like neurological PNPS secondary to lung adenocarcinoma. Interventions: The patient received intrathecal injections of pemetrexed and neurotrophic (vitamin B) therapy before ceasing chemoradiotherapy and chose cabozantinib on her own. Outcomes: Weakness of the proximal limbs, choking cough, and chewing problems did not improve significantly. Lessons: Although it is unclear why MG coexists with lung cancer, it is probable that MG is a paraneoplastic condition. Cerebrospinal fluid testing should be carried out along with electrophysiological, serological, and pharmacological procedures pertinent to the diagnosis of MG to thoroughly examine if people simultaneously experience MG-like PNPS and tumor growth. Starting immunotherapy and anticancer medication at the same time that tumor development and MG-like syndrome are discovered is crucial.


Introduction
Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated, complement-involved autoimmune neuropathy characterized by acetylcholine receptor antibody at the neuromuscular junction or other components of the postsynaptic muscle endplate, leading to neuromuscular transmission disorders. MG manifests several typical features: Partial or systemic skeletal muscle weakness and easy fatigue; Aggravated symptoms following activities, and; Marked relief of symptoms after rest or application of cholinesterase inhibitors. [1] MG can be diagnosed based on the typical characteristics of fluctuating myasthenia and either an electrophysiological or serum antibody detection test. [2] A fast-acting acetylcholinesterase inhibitor administered intravenously can instantly reverse MG muscle weakness, but this type of diagnosis method is more subjective.
Approximately 10% to 15% of patients with MG have thymoma, and 40% of thymoma patients eventually develop MG. [3] When combined with thymoma, MG exists as a paraneoplastic syndrome (PNPS) of thymoma. The association between MG and thymoma has been widely documented in the literature, [4][5][6] its association with lung cancer has not been clearly described. Herein, we report a case of MG coexisting with lung adenocarcinoma.

Case presentation
A 55-year-old female patient was admitted to the hospital on May 11, 2022, due to "weakened chewing accompanied by dizziness and unsteady walking for nearly half a year". Over the past 6 months, the patient gradually developed slurred speech, weakness in chewing, sporadic difficulty in swallowing, weakness in both lower limbs, and unsteady walking. Standing up from a sitting position made her dizziness more pronounced, which was likely caused by a shift in body position. The patient also had a dry nasal cavity that was prone to bleeding. In October 2011, the patient experienced right tinnitus, aural fullness, and hearing loss. She was diagnosed with "sudden deafness in the right ear" and received medical treatment. Subsequently, the hearing of the left ear gradually decreased, and no treatment was administered.
On March 11, 2022, because of an "obvious decline in hearing and vision and weakness of limbs for nearly 3 months", she returned to the hospital for medical investigation. Biological tests indicated that the cerebrospinal fluid (CSF) was colorless and transparent. The total number of white blood cells in the CSF was 23 × 10^6/L (0-5 × 10^6/L). The amount of protein was 0.63 g/L (0.15-0.45 g/L). Sugar and chloride levels were normal, and no tumor cells were observed. Today, the left ear is almost completely deaf, and the right ear functions to a very low degree, partly reserved, making communication almost impossible. She had been suffering from a lung tumor for nearly 4 years, and pathological examination revealed lung adenocarcinoma ( Fig. 1). Next-generation sequencing revealed an Epidermal Growth Factor Receptor missense mutation (NM_005228.3), c.2573T > G mutation (p. Leu 858Arg), and t790m. The patient was treated with osimertinib 160 mg qd for tumor-targeted therapy. No surgery was performed and there was no other medical history.  Vital signs were stable with postural hypotension. The patient had slurred speech, dysarthria, and decreased visual acuity. She could normally frown and close her eyes but closed her lips loosely without an obvious decrease in facial pain sensation. The patient also had weakness in her cheeks and chewing problems. She was completely deaf on her left side and partially deaf on her right side. The patient's gag reflex was sluggish. Her shoulder muscles were weak, and she could not extend her tongue past her lips, which was accompanied by atrophy and tremors. Limb proximal muscular strength was grade 4, and grade 5 distal muscular strength was present. The tendon reflexes of both upper and right lower extremities were +++, and her left lower extremity tendon reflexes were ++++. Both upper extremities passed the finger-nose test, and the heel-knee-shin test failed for both lower extremities. The pathological signs of the left lower extremity were suspiciously positive, Lasegue sign was (−), and meningeal irritation sign was (+).
Computed tomography of the lungs revealed thin-walled cavities in the lower lobe of the right lung and scattered solid nodules over the entire lung (Fig. 2). Magnetic resonance imaging scans of the brain, nasopharynx, cervical spine, and thoracic spinal cord revealed several lacunar cerebral infarctions, but no evident mass in the nasopharynx. There was an aberrant signal shadow in the right occipital lobe but no augmentation (Fig. 3). The results of the neostigmine test were negative. The following MG-related antibodies were absent: anti-acetylcholine receptor antibody, anti-muscle-specific tyrosine kinase autoantibody, anti-titin autoantibody, and anti-low-density lipoprotein receptor autoantibody. Anti-Hu, anti-Yo, anti-SOX1, and anti-voltage-gated calcium channel autoantibodies were negative for paraneoplastic antibodies.
Electromyography (EMG) revealed that some of the muscles examined had compound muscle action potential (CMAP) amplitudes that were attenuated by low-frequency stimulation (3 Hz) (the left abductor pollicis brevis muscle was attenuated by 46.2%, the right orbicularis oculi muscle was attenuated by 11.6%, and the right frontalis muscle was attenuated by 11.4%). High-frequency stimulation (30 Hz) did not significantly enhance the CMAP amplitude of the tested muscle (left   (Fig. 4). Cerebrospinal fluid examination was repeated, and based on the pathological findings, scattered, mildly atypical epithelioid cells and poorly differentiated adenocarcinomas were considered (Fig. 5).
The diagnoses were made as follows: Lung cancer with meningeal metastasis, multiple cranial nerve damage; Nervous system PNPS: secondary MG-like syndrome; Cerebellar and brainstem inflammation cannot be ruled out. Treatment should include supportive symptomatic care and immunotherapy in addition to treating the main tumor. [7] She was treated with neurotrophic (vitamin B group) therapy and advised to undergo hormone therapy, but the patient declined. After discharge, she received intrathecal chemotherapy with Pemetrexed in Xiehe, and tumor cells were again found in the CSF (Fig. 6). Subsequently, the patient stopped chemoradiotherapy and switched to cabozantinib on her own.
One month later, family members complained that although the patient's mental condition appeared to have marginally improved during chemotherapy, the patient's proximal limb weakness, choking cough, and chewing difficulties persisted.
Informed consent was obtained from the patient for publication of the findings of this case report.

Discussion
PNPS can affect various organ systems, most notably the endocrine, neurological, dermatological, rheumatological, and blood systems. They are brought on by hormones, peptides, or cytokines secreted by tumors, or by immune cross-reactivity between malignant and normal tissues. Tumor neural antibodies can often be detected in the serum, but 30% of paraneoplastic nerve system syndrome (PNS) patients fail to detect related antibodies. [7] Common PNS, such as central nervous system syndrome (e.g., limbic encephalitis and paraneoplastic subacute cerebellar degeneration), neuromuscular junctions (e.g., Lambert-Eaton myasthenic syndrome [LEMS]), peripheral nervous system (e.g., autonomic neuropathy and subacute sensory neuropathy), and retinopathy are often prone to occur. [8] A diagnosis of common PNS, such as LEMS and subacute cerebellar degeneration, was considered in this patient due to   Table 1 Reported cases of lung cancer with myasthenia gravis.  [20] 49 M SCLC Ptosis, progressive generalized muscle weakness, dyspnea  decreased muscle strength and ataxia, but this was not confirmed by related examinations. Re-frequency EMG revealed that CMAP waves were attenuated after low-frequency and high-frequency stimulation, which is consistent with the typical electrophysiological characteristics of MG. [9] Simultaneously, tumor cells were found in the CSF. Experts from multiple disciplines, including neurology, EMG, and oncology, have discussed this case. They ultimately agreed that cranial nerve injury caused by tumor infiltration could simultaneously involve the motor and sensory nerves. Owing to the influence of gravity, the latter group of cranial nerves is easily involved, and nerve injury is often asymmetric. There were pure sensory nerves II and VIII in this patient, mixed nerves V for the maxillary and mandibular branches, and X for cranial nerve injury. Multiple cranial nerve tumor infiltrations cannot be ruled out because MG syndrome is unable to fully explain the patient's symptoms. In addition, the patient had instability in walking, Romberg sign was unstable with both eyes open and closed, and tendon reflexes were hyperactive. Although no abnormality was found on head Magnetic resonance imaging, brainstem and cerebellar inflammation due to tumor infiltration could not be excluded. Taken together, our analysis and treatment provide new insights into our understanding of tumor-related MG-like neurological syndromes and the infiltration of cancer cells with neurological damage. In addition, brainstem and cerebellar inflammation caused by tumor infiltration cannot be completely excluded.
In small-cell lung cancer, PNPS is most frequently linked to lung cancer, with LEMS being the most prevalent PNS in the neuromuscular junction. When limiting the search time to 1990 to 2022, the search terms to "Lung Neoplasms" or "Adenocarcinoma of Lung" AND "myasthenia gravis" in Pubmed, most of the published cases are reports of other lung tumors complicated with MG, [10][11][12][13][14][15][16][17][18][19][20][21] but only 3 cases of lung adenocarcinoma [22][23][24] (Table 1). A thorough assessment of the literature led us to conclude that the causes of the coexistence of the 2 components have steadily become better understood over time, moving from an accidental phenomenon to an immunological problem to a paraneoplastic manifestation.
In the case described by Wang et al, [25] a patient was admitted to the hospital with ptosis and diplopia as the main complaints. Physical examination revealed lung cancer. Neostigmine text, MG, and paraneoplastic antibodies were all negative. EMG was not performed considering LEMS based on the symptoms alone. This finding is similar to the clinical features of our patient. Mesolella et al [26] also reported a patient with laryngeal neuroendocrine carcinoma who did not undergo EMG examination and did not have paraneoplastic or MG-related antibodies. LEMS was diagnosed based on typical symptoms of proximal muscle weakness and autonomic dysfunction. As a result, we assume that the lack of prior reports on lung cancer and MG may be attributed to physicians propensity to make diagnoses; hence, the likelihood of diagnostic bias cannot be completely ruled out. Even in cases where MG syndrome has been identified, many people do not undergo CSF testing, which makes it difficult for doctors to properly comprehend the patient's current condition. Furthermore, even in individuals with obvious imaging results and clinical symptoms, the positive diagnosis rate of CSF cytopathology is typically <50%, necessitating repeated testing. [27] Successful cancer treatment does not always result in improvements in neurological function, and the mainstay of PNS treatment is immune-modulating drugs. [8] In patients with PNS, combination therapy targeting malignancy and immunomodulation may help improve functional status. [28] After discharge, the patient only received chemotherapy and targeted therapy for tumor metastasis and lacked immunotherapy for MG, so her symptoms did not improve dramatically.
Thus, clinicians should initiate antitumor therapy and immunotherapy simultaneously when tumor progression and MG-like syndrome are detected, which may improve the prognosis of patients. Our clinical reports and investigations may provide new insights for the near future. This is because MG will become an item on the list of PNS associated with lung tumors, along with LEMS and paraneoplastic cerebellar degeneration.

Conclusion
We report a case of a Chinese female patient with lung adenocarcinoma who may be associated with MG, although the reason for their coexistence remains unknown. More fundamental studies on PNPS are needed to clarify the probable link between the 2. CSF testing is critical for determining tumor progression and requires several examinations.